GOT2 as a metabolic and immunologic target in pancreatic cancer

A new wave of scientific interest is spotlighting GOT2—glutamic-oxaloacetic transaminase 2—as a compelling therapeutic target in the fight against pancreatic cancer, one of the most lethal and treatment-resistant malignancies. This mitochondrial enzyme, deeply embedded in glutamine metabolism, plays a central role in sustaining cancer cell survival and growth. By regulating the malate-aspartate shuttle, GOT2 maintains cellular redox balance, generates essential metabolic intermediates, and influences energy production pathways that fuel tumor proliferation.

Unlike conventional approaches that often face resistance or poor efficacy, targeting GOT2 offers a multi-pronged strategy. Its activity is closely tied to the production of aspartate and α-ketoglutarate, vital for nucleotide and protein biosynthesis and ATP generation. These metabolic outputs are particularly essential for pancreatic cancer cells, which rely on a distinct, non-canonical glutamine metabolic route often driven by oncogenic KRAS mutations. Inhibiting GOT2 disrupts this pathway, leading to a collapse in redox equilibrium and accumulation of reactive oxygen species, thereby triggering cellular senescence and loss of proliferative capacity.

The enzyme's significance extends beyond metabolism. Recent discoveries have unveiled an unexpected nuclear function of GOT2, where it operates as a fatty acid transporter that activates PPARδ, a transcription factor involved in immune regulation. By promoting the expression of genes like PTGS2, CSF1, and REG3G, GOT2 fosters an immunosuppressive microenvironment, hindering T-cell infiltration and supporting tumor immune evasion. These dual functions position GOT2 as a linchpin at the intersection of metabolic programming and immune suppression, highlighting its appeal as a target for novel combination therapies.

Despite its critical role, pancreatic tumors exhibit adaptive resistance mechanisms. Some cancer cells circumvent GOT2 loss through macropinocytosis or by acquiring metabolites from cancer-associated fibroblasts, allowing them to replenish aspartate independently. Understanding and counteracting these resistance pathways is essential for optimizing GOT2-based treatments.

The pursuit of effective GOT2 inhibitors is ongoing, with promising early candidates like amino oxyacetate showing potential. Future research must refine these compounds and explore their integration with immunotherapies or redox-modulating treatments.